title: Identification of 2-piperidone as a biomarker of CYP2E1 activity through metabolomic phenotyping.
abstract: Cytochrome P450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of many low molecular weight toxicants and also an important contributor to oxidative stress. A noninvasive method to monitor CYP2E1 activity in vivo would be of great value for studying the role of CYP2E1 in chemical-induced toxicities and stress-related diseases. In this study, a mass spectrometry-based metabolomic approach was used to identify a metabolite biomarker of CYP2E1 through comparing the urine metabolomes of wild-type (WT), Cyp2e1-null, and CYP2E1-humanized mice. Metabolomic analysis with multivariate models of urine metabolites revealed a clear separation of Cyp2e1-null mice from WT and CYP2E1-humanized mice in the multivariate models of urine metabolomes. Subsequently, 2-piperidone was identified as a urinary metabolite that inversely correlated to the CYP2E1 activity in the three mouse lines. Backcrossing of WT and Cyp2e1-null mice, together with targeted analysis of 2-piperidone in mouse serum, confirmed the genotype dependency of 2-piperidone. The accumulation of 2-piperidone in the Cyp2e1-null mice was mainly caused by the changes in the biosynthesis and degradation of 2-piperidone because compared with the WT mice, the conversion of cadaverine to 2-piperidone was higher, whereas the metabolism of 2-piperidone to 6-hydroxy-2-piperidone was lower in the Cyp2e1-null mice. Overall, untargeted metabolomic analysis identified a correlation between 2-piperidone concentrations in urine and the expression and activity of CYP2E1, thus providing a noninvasive metabolite biomarker that can be potentially used in to monitor CYP2E1 activity.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Chi
authors.initials: C
authors.lastname: Chen
authors.forename: Krausz W
authors.initials: KW
authors.lastname: Kristopher
authors.forename: Soumen K
authors.initials: SK
authors.lastname: Manna
authors.forename: Mike
authors.initials: M
authors.lastname: Scerba
authors.forename: Fred K
authors.initials: FK
authors.lastname: Friedman
authors.forename: Hans
authors.initials: H
authors.lastname: Luecke
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Idle
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D015415:Biomarkers; D002103:Cadaverine / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D005260:Female; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D010641:Phenotype; D010881:Piperidones / Q000652:urine*; D053719:Tandem Mass Spectrometry
chemical_list: D015415:Biomarkers; D010881:Piperidones; D019392:Cytochrome P-450 CYP2E1; D002103:Cadaverine; C043384:2-piperidone
keywords: 2-piperidone; CYP2E1; biomarker; cadaverine.; metabolomics